修回日期: 2011-10-18
接受日期: 2011-11-04
在线出版日期: 2011-11-18
甲基化是一种以胞嘧啶为基础的DNA改变, 他从表观遗传的角度调控许多真核生物的生长代谢, 并对正常生物学行为和疾病的发生具有重要意义. DNA甲基化是一种重要的基因表观遗传改变, 调控细胞的许多进程. 已经发现越来越多的人类疾病包括癌症与异常的DNA甲基化有关. 最近快速发展的癌症表观遗传学领域揭示了涉及癌症表观遗传的每一个组件的广泛重组现象, 如DNA脱甲基化. 本文主要综述了当前DNA甲基化改变在胃癌与正常组织细胞的研究比较, 他在胃癌发生发展中的角色及利用这些已知指导更有效的治疗趋势.
引文著录: 隋红, 王凯冰, 白玉贤. DNA甲基化与胃癌的研究进展. 世界华人消化杂志 2011; 19(32): 3347-3352
Revised: October 18, 2011
Accepted: November 4, 2011
Published online: November 18, 2011
Methylation of cytosine bases in DNA provides a layer of epigenetic control in many eukaryotes that has important implications for normal biology and disease. DNA methylation is a crucial epigenetic modification of the genome that is involved in regulating many cellular processes. A growing number of human diseases including cancer have been found to be associated with aberrant DNA methylation. Recent advancements in the rapidly evolving field of cancer epigenetics have described extensive reprogramming of every component of the epigenetic machinery in cancer, such as DNA demethylation. In this review, we discuss the current understanding of alterations in DNA methylation composing the epigenetic landscape that occurs in gastric cancer compared with normal cells, the roles of these changes in gastric cancer initiation and progression, and the potential use of this knowledge in designing more effective treatment strategies.
- Citation: Sui H, Wang KB, Bai YX. DNA methylation and gastric cancer. Shijie Huaren Xiaohua Zazhi 2011; 19(32): 3347-3352
- URL: https://www.wjgnet.com/1009-3079/full/v19/i32/3347.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v19.i32.3347
DNA甲基化是指基因组中CpG岛的胞嘧啶环上的第5位碳原子的甲基化, 可标志为5mC[1]. 目前对肿瘤细胞基因组DNA甲基化的发现包括[2]: (1)基因组的广泛低甲基化是肿瘤细胞的一个普遍特征; (2)CpG岛低甲基化, 在许多肿瘤组织中, 原先高甲基化的CpG岛成为低甲基化, 同时伴有其邻近基因的活化; (3)肿瘤抑制基因启动子区的高甲基化可使其沉默、失活致表达产物减少或丧失; (4)基因印记丢失, 印记基因是高甲基化不表达的, 丢失甲基化则会使之活化, 称为印记丢失; (5)启动子区甲基化修饰是可复的, 这也可解释肿瘤组织中的癌细胞表型的不断转换[3]. DNA甲基化属表观遗传学范畴, 已经证实由遗传基因和表观遗传学异常所致的抑癌基因的失活和癌基因的激活在癌发生中意义重大. 过去人们一直认为基因突变是肿瘤病因学的关键所在, 体细胞的抑癌基因突变与肿瘤发生密切相关. Feil[4]最近报道, 环境因素、饮食习惯等可以在不改变DNA序列的情况下影响相关基因的转录和表达, 不利环境因素和饮食习惯可以通过DNA甲基化和组蛋白的共价修饰来扰乱基因的正常表达. 随着对肿瘤生物学行为的深入了解, 越来越多的迹象表明启动子区的异常甲基化和组蛋白修饰所致的这些基因的表观沉默在癌发生和转移中必不可少. 例如肿瘤细胞系的抑癌基因启动子区的异常DNA甲基化在蛋白水平而不是在基因组水平上下调其表达引起改变[5].
目前, 胃癌的发病机制不完全清楚. 同其他肿瘤类似, 胃癌的发生亦是多步骤、多阶段、多基因改变与表基因改变的复杂过程[6-9]. 胃癌的病因主要包括以下几个方面: (1)胃癌发病与环境因素有关, 其中包括食物、土壤、水源等; (2)胃癌患者家族中的发病率比对照组高4倍. 日本高发区的土人移居美国后, 其发病率仍高于当地的白种人, 表明胃癌的发生与遗传因素有关; (3)癌前疾病: 如慢性萎缩性胃炎、胃息肉、良性胃溃疡、巨大胃黏膜皱襞症(Menetrier病)、异形增生与间变、肠化生等. 胃癌发病的这种独特病因体系提示: 胃癌是研究肿瘤表观遗传修饰的最佳模型之一.
20世纪80年代, Kliasheva发现胃癌组织和十二指肠溃疡中DNA组的胞嘧啶甲基化差异现象; 1999年, 第一个DNA错配修复基因hMSH2和hMLH1启动子区甲基化在胃癌中确认[10]. 自从最初的通过甲基化异常筛选抑癌基因开始, 胃癌相关基因甲基化在胃癌发生发展中的作用成为人类认识肿瘤的又一焦点. 胃癌组织中hMSH2基因启动子区高甲基化, 与癌旁组、慢性萎缩性胃炎组、慢性浅表性胃炎组3组甲基化水平相比, 差别具有统计学意义. 由此可推断胃癌组织中hMSH2基因启动子区高甲基化可能是导致其错配修复功能缺陷的重要原因之一; 而错配修复功能缺陷在胃癌的发生中起着重要作用, 但可能与其发展关系不大[11-26]. ZIC1(Zic family member 1, odd-paired Drosophila homolog)的启动子区过甲基化使该基因失活促进胃癌发生, ZIC1由此被认定为新的抑癌基因, 这种过甲基化行为在胃癌组织常见, 并且和正常胃组织中存在差异. 启动子区过甲基化使ZIC1表达下调与胃癌发生密切相关, 而ZIC1基因发挥抑癌作用表现为使胃癌细胞阻滞在S期[27]. P16基因甲基化则在淋巴结受侵的胃癌中常见[28-33]. P16基因的甲基化与肠型胃癌和贲门部定位相关, SHP1甲基化与EBV感染密切相关, APC和RAR-beta2甲基化提示患者预后相对较好[34,35]. Hino则认为PTEN基因启动子区的异常甲基化和基因缺失与一种EB病毒(Epstein-Barr virus, EBV)相关的胃癌发生密切相关, 实验通过甲基化特异性PCR和免疫组织化学方法证实, 而且这种异常在胃癌细胞系MKN-1和MKN-7中可见. 进一步研究发现, 病毒的潜伏膜蛋白2A(latent membrane protein 2A, LMP2A)引起信号传导及转录活化子3(signal transducer and activator of transcription 3, STAT3)磷酸化成pSTAT3, 后者激活DNA甲基转移酶1(DNA methyltransferase 1, DNMT1)转录, 通过PTEN基因启动子区CpG岛甲基化最终使EBV相关胃癌的PTEN基因表达缺失[36]. 目前研究较多的还有PCDH10, MINT25等[37-45]. 而环指蛋白180(RNF180)启动子区的甲基化则使环指蛋白180(RNF180)表达下调或缺失, 并与胃癌患者的预后不良有关[46]. Kim等[47]检测74名胃癌患者组织原发灶和转移灶的ADAM23、CDH1、FHIT、FLNC、GSTP1、ITGA4、LOX、RUNX3、THBS1、TIMP3和UCHL1的甲基化差异, 发现FLNC甲基化可作为胃癌淋巴结转移的独立预后标记. Jee等[48]通过对143个肿瘤相关基因筛查, 发现TFPI2、GPX3、GPX1、IGFBP6、IRF7和DMRT1在胃癌细胞系和152名胃癌患者肿瘤组织中普遍存在, 多变量分析TFPI2甲基化为特异和独立的预后不良指标.
幽门螺杆菌(Helicobacter pylori, H. pylori)感染主要发生在儿童期, 感染可能会持续存在并伴随一生, 直到抗生素干预根除. H. pylori感染引起启动子区CpG岛甲基化并定位于胃癌表皮细胞[49-55]. Shin等[50]研究成年人和儿童胃黏膜甲基化状态, 比较基因的甲基化水平与H. pylori阳性和阴性的关系, 发现H. pylori感染的儿童, 其甲基化基因的平均水平高于H. pylori阴性的儿童(3.4 vs 0.3, P<0.001), 这种差异在成年人中也是如此. 其中, 基因CDH1、DAPK1、CRABP1、GRIN2B、TIMP3、CALCA和TWIST1在H. pylori阳性的儿童中呈显著的高甲基化现象. 可以认为发生于儿童胃黏膜的CpG岛甲基化与H. pylori感染密切相关, 而且出现高甲基化的基因在成年人和儿童中相似. Shin[56]研究组认为基因组DNA广泛的低甲基化现象是H. pylori相关胃癌发生过程的早期事件. Alves[57]研究认为启动子区甲基化致抑癌基因COX-2、HMLH1和CDKN2A失活与H. pylori阳性的胃癌患者的临床病理关系, 发现这些基因的甲基化与蛋白表达存在强烈的负相关, 胃贲门癌患者p16(INK4A)的负相关最为突出. 而在非贲门癌患者, 亚型不同基因表达存在差异. 肠型胃癌HMLH1基因甲基化致该基因失活最显著, 弥漫型胃癌CDKN2A基因甲基化致该基因失活最显著. COX-2和HMLH1甲基化与H. pylorivacA s1亚型密切相关(分别为P = 0.025和0.047), 不伴有被测抑癌基因甲基化的胃癌则与鞭毛亚单位基因(flaA)密切相关.
Bernal[58]通过对32例胃癌患者的原发肿瘤组织, 应用甲基化特异性PCR方法分析24个基因的DNA甲基化模式, 结果50%以上患者的11个基因有高度甲基化(APC、SHP1、E-cadherin、ER、Reprimo、SEMA3B、3OST2、p14、p15、DAPK和p16). 8个基因(BRCA1、p73、RAR beta、hMLH1、RIZI、RUNX3、MGMT和TIMP3)与一种特殊类型的胃癌即印戒细胞癌在统计学意义上具有相关性, 配对的血浆标本中APC和Reprimo有高频率的甲基化. 和胃癌患者血浆标本比较, 无症状的对照组只有Reprimo甲基化的频率较低. 由此筛选出Reprimo是胃癌早期检测的潜在生物标记物. Cheung在7种胃癌细胞系中检测环指蛋白180(RNF180)的表达, 结果RNF180在其中的6种细胞系存在表达沉默, 并且在肿瘤组织中表达下调, 与癌旁正常组织相比差异显著. 相继检测发现RNF180的启动子区在胃癌组织有明显的甲基化达76%(150/198), 而在正常组织中没有. 胃癌患者血浆中RNF180的启动子区甲基化达56%, 而在健康的对照组血浆中未检测到甲基化[58]. 由此推荐RNF180可作为胃癌筛查的生物标志物.
借鉴结直肠癌、乳腺和妇科肿瘤相关基因DNA甲基化检测的研究经验, 胃癌相关基因的甲基化检测主要通过胃癌组织学标本、外周血标本, 包括外周血血浆、血清[59-62]. 最近Terry等[63]从细胞水平提出DNA甲基化检测与疾病包括恶性肿瘤, 研究涉及到肠癌、胃癌、膀胱癌、乳腺癌和头颈部癌等, 以及某些内科疾病诸如精神分裂症和骨髓异常增生症的关系; 研究人类外周血白细胞的特定位点的甲基化与环境暴露、风险因素和人口学以及疾病三者之间的关系, 认为白细胞特定位点的甲基化与疾病的风险因素存在密切关系. 但是能否作为随时监测的生物学标记物还需要前瞻性研究的验证[64]. 鉴于DNA甲基化发生于癌变过程的早期, 为了评估腹水中细胞的甲基化是否可作为胃癌腹膜微转移的临床早期诊断途径, 最近有学者[65]报道分别收集癌组织未超过固有肌层、超过固有肌层和已经证实腹膜转移的3组胃癌患者的腹腔灌洗液细胞, 其中癌组织未超过固有肌层、超过固有肌层的2组无论腹膜细胞学还是组织学均无癌细胞; 检测BNIP3、CHFR、CYP1B1、MINT25、SFRP2和RASSF2基因的甲基化在3组中的差异, 结果发现3组中6个基因均存在甲基化, 而且病理分期越晚, 甲基化的程度和频率越高. 随访发现, 癌组织超过固有肌层的胃癌患者伴有甲基化的发生腹膜转移的几率明显高于那些不伴有甲基化的患者. 由此推断腹腔灌洗液甲基化检测联合细胞学检查或许可以提高胃癌腹腔灌洗液中癌细胞的阳性检出率, 有助于筛查腹膜转移的患者或作为高危因素指导后续治疗. 为了提高筛查的实用性, 最近有学者报道从低分化弥漫型胃癌患者的胃液中可以检测到E-cadherin(CDH1)基因启动子区的高甲基化, 与对照组有统计学差异, 显示出该途径的乐观前景. 但由于胃液的收集和DNA提取与操作者的技术水平相关, 使得这一项目的深入研究受到限制. Nagasaka[66]研究团队探索新的非侵入性的筛查手段降低胃肠道肿瘤的致死率,结果从57.1%的胃癌患者粪便排泄物中检测到RASSF2和SFRP2基因启动子区DNA甲基化, 且与无相关疾病的病例有统计学差异. 尽管该方法具有较强的实用性, 但是还没有后续的平行对照研究来证实其特异性和敏感性.
表观遗传修饰具有可逆性, 因此在肿瘤或癌前病变中可通过去甲基化或乙酰化的方法恢复某些关键性抑癌基因的表达, 从而达到预防或治疗肿瘤的目的. 阿扎胞苷和5-aza-dC通过共价键与DNA甲基转移酶(DNMT)结合可形成不可逆的复合物, 从而抑制其活性使基因组整体甲基化水平降低, 进而重新激活由于高甲基化而失活的关键性抑癌基因. 目前一种新的DNMT抑制剂zebularine正在研究之中.
胃肠道恶性肿瘤是全世界最常见的恶性肿瘤, 且这些肿瘤的诊断与监测手段仍处于较低水平, 由此识别新的生物标记物应用于肿瘤的不同阶段无疑是雪中送炭. 目前, 特定基因的DNA甲基化致使基因失活在胃肠道肿瘤已被公认. 新领域生物的DNA甲基化检测有可能更好的方法筛选、早期诊断、疾病进展和治疗反应的预测胃肠肿瘤的治疗[67-69].
DNA甲基化是一种重要的基因表观遗传的改变, 调控细胞的许多进程. 快速发展的癌症的表观遗传学领域揭示了涉及癌症表观遗传的每一个组件的广泛重组现象, DNA甲基化在肿瘤的发生、发展均起重要作用. 随着对其研究的深入, 人们在对胃癌的发生机制有更深入了解的同时, DNA甲基化在胃癌的诊断、治疗以及判断预后方面都给人们提供了新的方法和途径.
DNA甲基化是一种重要的基因表观遗传改变, 调控细胞的许多进程. 而且越来越多的人类疾病,包括癌症已经发现与异常的DNA甲基化有关.
肖恩华, 教授, 中南大学湘雅二医院放射教研室
研发前沿 快速发展的癌症表观遗传学领域揭示了涉及癌症表观遗传的每一个组件的广泛重组现象, 如DNA脱甲基化. 在本文中, 我们讨论当前DNA甲基化改变在胃癌与正常组织细胞相比的研究, 这些变化在胃癌发生发展中的角色及利用这些已知指导更有效的治疗的趋势.
文章中将DNA甲基化在H. pylori相关胃癌和DNA甲基化在胃癌早诊中的研究以及检测取材上作详细综述. 不同于以往文章主要综述、临床病理关系或研究方法.
本文为DNA甲基化在胃癌诊断和治疗上提供新的指导和策略.
本综述选题新, 有一定深度与广度.
编辑: 曹丽鸥 电编:闫晋利
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